Abstract D051: Targeting ubiquitin receptor ADRM1 for the treatment of quadruple-negative breast cancer

Quadruple Negative Breast cancer (QNBC) is a subtype of Triple Negative Breast Cancer (TNBC) with loss of Androgen receptor (AR). We determined the expression of AR and its relationship to breast cancer subtypes, using Gene Expression Omnibus (GEO) profiles that contained racial and clinical outcomes data totaling 1061 patients. Expression of the AR protein level was confirmed in an additional multi-institutional cohort of 197 breast cancer patients, for a total of 1258 patient evaluated. Relative to White women, African American women had higher percentage (81%) of AR-negative tumors, and, for both races, AR-negative tumors correlated with the basal subtype, a shorter time to progression, and worse overall survival (OS) compared to White women. Currently available treatments are unable to eradicate metastatic breast cancer (TNBC and QNBC), and median survival for these patients is only 2–4 years. Improving the survival rates for metastatic disease has been the subject of intense investigation, and new agents and strategies are actively being evaluated. Targeting the UPS (Ubiquitin-proteasome system) with small molecules can an effective can cancer therapy. We have developed an orally-available proteasome inhibitor bis-benzylidine piperidone (RA190), that binds to the ubiquitin receptor RPN13/ADRM1 on the 19S regulatory particle of the proteasome and directly kills cancer cells by triggering proteotoxic stress. The objective of this study is to investigate the expression of ADRM1 in QNBC patients and target ADRM1 with RA190 for the treatment of QNBC., We used forest plot analysis of TCGA patient samples to determine the expression of Ubiquitin receptor ADRM1, and invitro assays to find the sensitivity of RA190 against AR-positive and AR-Negative breast cancer cells. Our results indicate that ADRM1 is significantly elevated and in QNBC breast tumors of African American patients. Our cell culture data show that, AR-positive and AR-Negative breast cancer cells have differential sensitivity in IC50 values to inhibitor RA190. Our findings will advance our knowledge of vulnerable pathways in QNBC/TNBCs optimal control and reveal if this mechanism is more likely to occur in African American patients. Citation Format: Balasubramanyam Karanam, Ravi Anchoori, Richard Roden, Clayton Yates. Targeting ubiquitin receptor ADRM1 for the treatment of quadruple-negative breast cancer [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D051.